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S1322 Effects of Lubiprostone on Serotonin Release From the Intestinal Mucosa
investigating the colon (eg faecal calprotectin) should be more available, although there were reassuringly few repeated colonoscopies. The low rate of referral to dietetics and especially psychology suggests underutilisation of these services.
S1320 Multi-Center, 4-Week, Double-Blind, Randomized, Placebo-Controlled Trial of Sodium Picosulfate (SPS) in Patients With Chronic Constipation Stefan A. Mueller-Lissner, Michael A. Kamm, Arnold Wald, Ulrika Hinkel, Ursula Koehler, Erika Richter, Juergen Bubeck
AGA Abstracts
S1318
INTRODUCTION: High quality trials assessing the efficacy and safety of stimulant laxatives are lacking. AIMS & METHODS: A randomized, double-blind, multi-center, placebo-controlled study assessed the efficacy and safety of 4-week treatment with SPS drops (up to 10 mg, once daily) in patients with chronic constipation (CC) (ROME III diagnostic criteria). Patients were recruited from primary care practices and randomized in a 2:1 ratio to SPS or placebo for 4 weeks following a 2-week baseline without study medication. Efficacy data were recorded in an electronic diary daily by the patients. RESULTS: 367 patients were randomized, 233 patients received SPS and 134 placebo. The mean number of complete spontaneous bowel movements (CSBMs) per week during the 4 weeks of treatment (= primary endpoint) increased with SPS from 0.9±0.1 (mean±SE) to 3.6±0.3 and only from 1.1±0.1 to 1.8±0.3 on placebo. The mean difference between treatment groups was 1.8±0.3 (p<0.0001). The results for the secondary endpoints: number of CSBM, total bowel frequency, and constipation-related symptoms were all statistically significantly in favor of SPS. Assessment of Quality of Life (QoL) by the constipation-related PAC−QOL© questionnaire showed significant improvement in SPS-treated patients compared to placebo. The final global efficacy assessed by the investigator after the treatment period was rated as ‘Good' or ‘Satisfactory' for 87% of the SPS-treated patients and 48% on placebo (p<0.0001); patient ratings were similar (88% SPS vs. 48%; p<0.0001). SPS treatment was well tolerated with a similar frequency of adverse events in both groups. CONCLUSION: Contrary to the often-stated view that stimulant laxatives have limited or non-sustained efficacy, sodium picosulfate is an effective, well tolerated, and safe treatment for chronic constipation.
STW5 Leads to Changes in Immunologic Response, as Assessed by Cytokine Secretion, in Healthy Controls, but Not Subjects With Irritable Bowel Syndrome (IBS) Jenny Persson, Gerald Holtmann, Amelia N. Pilichiewicz, Montri Gururatsakul, MingXian Yan, Edmund C. Khoo, Judith Gapasin, Charlotte Goess, Nora B. Zschau, Lee-Anne Faraguna, Birgit Adam, Tobias Liebregts, Richard H. Holloway, Jane M. Andrews Background/Objectives: The cause of IBS is unknown but altered immune responses are thought to play a role. Previously, differences in cytokine release between healthy controls (HC) and subjects with IBS have been shown, and have also correlated with symptoms in some IBS-affected subjects Methods: In a pilot study to assess the effect of STW5 on immune response in IBS patients, subjects and HC received STW5 or placebo (20 drops, 3 x daily, x 14 days) in a double-blind, randomized, cross-over design with 7-14 days washout between treatments. Blood was collected at screening and after each treatment phase. Immune responsiveness was assessed by cytokine release from peripheral blood mononuclear cells (PBMC). PBMC were isolated and stored until each subject completed the study. PBMCs were then cultured for 24 hours and cytokines measured in conditioned culture medium. Concentrations of pro-inflammatory cytokines; tumor necrosis factor-α (TNF-α), interleukin 1-β (IL-1β), interleukin-6 (IL-6), and the anti-inflammatory cytokine interleukin-10 (IL-10) were measured by ELISA. Results: 23 IBS patients (17F; age 44±3 yrs) and 25 HC (16F; 35±3 yrs) were recruited. No HC had IBS or functional dyspepsia. Cytokine concentrations at baseline showed no differences between HC and IBS patients. To adjust for inter-subject variability, baseline cytokine secretion was normalized to 100% and subsequent measures expressed as percentage change from this. During both STW5 and placebo HC showed a more consistent pattern of cytokine release than IBS subjects; such that they had significant increases in IL-6 and IL-10 in response to both STW5 and placebo; and significantly increased TNF-α and IL-1β in response to placebo, but not STW5. IBS subjects did not have any significant change from baseline cytokine levels in response to either treatment due to greater inter-individual variability in responses. Conclusion: In HC's STW5 appears to have an antiinflammatory effect, mitigating the TNF-a and IL-1b secretion that is seen during placebo. However, cytokine release in IBS showed no such pattern suggesting dysregulation of cytokine responses. Subgroup analysis, with a larger IBS sample, may further elucidate this variability.
S1321 Stimulant Laxatives are Effective in Chronic Constipation: Multi-Center, 4Week, Double-Blind, Randomized, Placebo-Controlled Trial of Bisacodyl Michael A. Kamm, Stefan A. Mueller-Lissner, Arnold Wald, Ulrika Hinkel, Erika Richter, Ros Swallow, Juergen Bubeck INTRODUCTION: Although stimulant laxatives have been used for many years, their clinical value has been questioned and high quality trials assessing their efficacy are lacking. AIMS & METHODS: This randomized, double-blind, multi-center, placebo-controlled, parallel group study aimed to determine the efficacy and safety of 4 weeks of treatment with oral bisacodyl tablets 10 mg, once daily, in patients with chronic constipation (defined by ROME III criteria). Patients were randomized 2:1 to bisacodyl or placebo for 4 weeks following 2 week baseline period without study medication. Efficacy data were recorded daily in an electronic diary by patients. RESULTS: 368 patients were randomised to the two treatment groups: 247 patients received bisacodyl and 121 placebo. The mean number of complete spontaneous bowel movements (CSBMs) per week during the 4 weeks of treatment (= primary endpoint) increased in the bisacodyl group from 1.1±0.1 (mean±SE) to 5.2±0.3 and in the placebo group from 1.1±0.1 to 1.9±0.3. The adjusted mean difference between treatment groups was 3.3±0.4 (p<0.0001). Secondary endpoints of number of CSBM, number of SBM, and a range of constipation-associated symptoms were all statistically significant in favour of bisacodyl. Quality-of-life (PAC−QOL©) change from baseline for the overall score as well as single scores ‘Worries and concerns', ‘Physical discomfort', ‘Psychosocial discomfort' and ‘Satisfaction' were all significantly improved in favour of the bisacodyl group (for ‘Psychosocial discomfort': p=0.007; for all others p<0.0001). Treatment with bisacodyl was well tolerated. All SAEs (occurring in 2 patients on placebo and 1 patient on bisacodyl) were assessed as non-drug-related. CONCLUSION: Oral bisacodyl is an effective, welltolerated and safe treatment for patients with chronic constipation. It increases bowel frequency, frequency of complete bowel actions, and improves the associated symptoms of constipation and disease-related quality of life.
Cytokine secretion as % change from baseline (mean, +/-SEM) * P ≤ 0.05 significant compared to baseline. S1319 Prokinetic Effects of Lubiprostone on Gastrointestinal Motility in Dogs Jun Song, Jieyun Yin, Hanaa S. Sallam, Ruixing Zhang, Jiande Chen Aims: The study aimed to explore possible prokinetic effects of a chloride channel activator, Lubiprostone on gastrointestinal motility in healthy dogs. Methods: Six healthy female hound dogs were chronically implanted with two cannulas, one at the proximate jejunum and the other at the proximate ascending colon. A number of experiments were performed to access the effects of Lubiprostone (Lub.) on gastric emptying, small intestinal transit and contractions, and colon transit and contractions in these dogs. Gastric emptying of solids was determined by the collection of gastric chyme from the jejunum cannula after ingestion of a can of dog food in three randomized sessions (control and 2 doses of Lub.). Small bowel transit time was studied by observing the time from the injection of phenol red into the jejunum cannula till the first appearance of phenol red from the colon cannula. Colon transit was evaluated by inserting radiopaque markers into the colon from the colon cannula and taking X-ray pictures at 2,4 and 6hrs after the insertion of the markers. Small bowel and colon contractions were measured via a water-perfuse catheter inserted into the small bowel or colon via the corresponding cannula. Each of the experiments was performed in two or three randomized sessions: control, Lub.24μg, or/and Lub.48μg. Lub. was orally administrated 45 minutes before the experiment. Results:1) Lub. significantly accelerated gastric emptying of solids at a dose of 48μg (empertying at 120min: 72.2±7.7% vs. 53.1±5.8% with control, p=0.02 ) but not at 24μg. 2) Lub. significantly reduced small bowel transit time at both 48μg (82.5±31.3 min vs. 137.8±19.3 min, P<0.05) and 24μg (71.0±28.9 min, P<0.05 vs. control). 3) Lub. at 48μg significantly accelerated colonic transit. The geometric center value at 4hrs after the insertion of the markers was 5.1±0.3 with Lub. and 4.3±0.4 in the control session (P=0.047). 4) The manometric studies showed that lub. 48μg significantly increased postprandial small bowel motility index (8.8±0.6 vs.13.2±1.5, P=0.006) and colon motility index (5.8±0.5 vs. 7.3±0.8, P=0.048). Conclusion: Lubiprostone accelerates gastric emptying of solids, small bowel transit and colon transit, and enhances small intestinal contractions and colon contractions in the postprandial states. Theses findings suggest that Lubiprostone may be used to treat patients with gastrointestinal motility disorders. More studies are needed to investigate the mechanisms involved in the prokinetic effects of Lubiprostone.
AGA Abstracts
S1322 Effects of Lubiprostone on Serotonin Release From the Intestinal Mucosa Elice M. Brooks, Jill M. Hoffman, Vanessa W. Hui, Gary M. Mawe Lubiprostone is a selective activator of type-2 voltage-activated chloride channels (ClC-2) located on intestinal epithelial cells, and it alleviates constipation by enhancing intestinal secretion. Lubiprostone is generally well tolerated, but nausea is the most frequently occurring side effect. Serotonin (5-hydroxytryptamine; 5-HT) release from the mucosa of the upper gastrointestinal tract can induce nausea by activating 5-HT receptors on vagal afferent fibers, and this is alleviated by treatment with 5-HT3 receptor antagonists. Serotonin release from enterochromaffin (EC) cells also stimulates secretion and motility via activation of intrinsic neural reflexes. Therefore, this study was designed to test whether EC cells express ClC-2 channels, and if lubiprostone causes release of 5-HT from these cells. Double-label immunohistochemistry for ClC-2 and 5-HT was performed to determine whether ClC-2 channels are located on EC cells, and enzyme immunoassay was used to test whether lubiprostone elicits 5-HT release from the intestinal mucosa. Immunohistochemistry involving the use of two different polyclonal antisera directed against the ClC-2 channel revealed ClC-2 immunoreactivity on EC cells in the mucosa of the human rectum and guinea pig distal colon. In the 5-HT release studies, 5 minute exposure to lubiprostone (1 μM) did not stimulate 5-HT release in human rectal mucosal biopsy specimens or guinea pig duodenal mucosal preparations, but lubiprostone did cause a slight but significant increase in 5-HT release in guinea pig distal colon mucosal samples. The 5-HT release elicited by lubiprostone in the distal colon preparations was less than that detected in positive control experiments involving mechanical stimulation (agitated on a vortex) or syrup of ipecac (1:10 dilution in Krebs solution). In conclusion, these data indicate that EC cells express ClC-2 channels, but activation of these channels by lubiprostone is not a very effective trigger for 5-HT release. This study was supported by Takeda Pharmaceuticals and NIH grant DK62267.
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S1320 Multi-Center, 4-Week, Double-Blind, Randomized, Placebo-Controlled Trial of Sodium Picosulfate (SPS) in Patients With Chronic Constipation Stefan A. Mueller-Lissner, Michael A. Kamm, Arnold Wald, Ulrika Hinkel, Ursula Koehler, Erika Richter, Juergen Bubeck
AGA Abstracts
S1318
INTRODUCTION: High quality trials assessing the efficacy and safety of stimulant laxatives are lacking. AIMS & METHODS: A randomized, double-blind, multi-center, placebo-controlled study assessed the efficacy and safety of 4-week treatment with SPS drops (up to 10 mg, once daily) in patients with chronic constipation (CC) (ROME III diagnostic criteria). Patients were recruited from primary care practices and randomized in a 2:1 ratio to SPS or placebo for 4 weeks following a 2-week baseline without study medication. Efficacy data were recorded in an electronic diary daily by the patients. RESULTS: 367 patients were randomized, 233 patients received SPS and 134 placebo. The mean number of complete spontaneous bowel movements (CSBMs) per week during the 4 weeks of treatment (= primary endpoint) increased with SPS from 0.9±0.1 (mean±SE) to 3.6±0.3 and only from 1.1±0.1 to 1.8±0.3 on placebo. The mean difference between treatment groups was 1.8±0.3 (p<0.0001). The results for the secondary endpoints: number of CSBM, total bowel frequency, and constipation-related symptoms were all statistically significantly in favor of SPS. Assessment of Quality of Life (QoL) by the constipation-related PAC−QOL© questionnaire showed significant improvement in SPS-treated patients compared to placebo. The final global efficacy assessed by the investigator after the treatment period was rated as ‘Good' or ‘Satisfactory' for 87% of the SPS-treated patients and 48% on placebo (p<0.0001); patient ratings were similar (88% SPS vs. 48%; p<0.0001). SPS treatment was well tolerated with a similar frequency of adverse events in both groups. CONCLUSION: Contrary to the often-stated view that stimulant laxatives have limited or non-sustained efficacy, sodium picosulfate is an effective, well tolerated, and safe treatment for chronic constipation.
STW5 Leads to Changes in Immunologic Response, as Assessed by Cytokine Secretion, in Healthy Controls, but Not Subjects With Irritable Bowel Syndrome (IBS) Jenny Persson, Gerald Holtmann, Amelia N. Pilichiewicz, Montri Gururatsakul, MingXian Yan, Edmund C. Khoo, Judith Gapasin, Charlotte Goess, Nora B. Zschau, Lee-Anne Faraguna, Birgit Adam, Tobias Liebregts, Richard H. Holloway, Jane M. Andrews Background/Objectives: The cause of IBS is unknown but altered immune responses are thought to play a role. Previously, differences in cytokine release between healthy controls (HC) and subjects with IBS have been shown, and have also correlated with symptoms in some IBS-affected subjects Methods: In a pilot study to assess the effect of STW5 on immune response in IBS patients, subjects and HC received STW5 or placebo (20 drops, 3 x daily, x 14 days) in a double-blind, randomized, cross-over design with 7-14 days washout between treatments. Blood was collected at screening and after each treatment phase. Immune responsiveness was assessed by cytokine release from peripheral blood mononuclear cells (PBMC). PBMC were isolated and stored until each subject completed the study. PBMCs were then cultured for 24 hours and cytokines measured in conditioned culture medium. Concentrations of pro-inflammatory cytokines; tumor necrosis factor-α (TNF-α), interleukin 1-β (IL-1β), interleukin-6 (IL-6), and the anti-inflammatory cytokine interleukin-10 (IL-10) were measured by ELISA. Results: 23 IBS patients (17F; age 44±3 yrs) and 25 HC (16F; 35±3 yrs) were recruited. No HC had IBS or functional dyspepsia. Cytokine concentrations at baseline showed no differences between HC and IBS patients. To adjust for inter-subject variability, baseline cytokine secretion was normalized to 100% and subsequent measures expressed as percentage change from this. During both STW5 and placebo HC showed a more consistent pattern of cytokine release than IBS subjects; such that they had significant increases in IL-6 and IL-10 in response to both STW5 and placebo; and significantly increased TNF-α and IL-1β in response to placebo, but not STW5. IBS subjects did not have any significant change from baseline cytokine levels in response to either treatment due to greater inter-individual variability in responses. Conclusion: In HC's STW5 appears to have an antiinflammatory effect, mitigating the TNF-a and IL-1b secretion that is seen during placebo. However, cytokine release in IBS showed no such pattern suggesting dysregulation of cytokine responses. Subgroup analysis, with a larger IBS sample, may further elucidate this variability.
S1321 Stimulant Laxatives are Effective in Chronic Constipation: Multi-Center, 4Week, Double-Blind, Randomized, Placebo-Controlled Trial of Bisacodyl Michael A. Kamm, Stefan A. Mueller-Lissner, Arnold Wald, Ulrika Hinkel, Erika Richter, Ros Swallow, Juergen Bubeck INTRODUCTION: Although stimulant laxatives have been used for many years, their clinical value has been questioned and high quality trials assessing their efficacy are lacking. AIMS & METHODS: This randomized, double-blind, multi-center, placebo-controlled, parallel group study aimed to determine the efficacy and safety of 4 weeks of treatment with oral bisacodyl tablets 10 mg, once daily, in patients with chronic constipation (defined by ROME III criteria). Patients were randomized 2:1 to bisacodyl or placebo for 4 weeks following 2 week baseline period without study medication. Efficacy data were recorded daily in an electronic diary by patients. RESULTS: 368 patients were randomised to the two treatment groups: 247 patients received bisacodyl and 121 placebo. The mean number of complete spontaneous bowel movements (CSBMs) per week during the 4 weeks of treatment (= primary endpoint) increased in the bisacodyl group from 1.1±0.1 (mean±SE) to 5.2±0.3 and in the placebo group from 1.1±0.1 to 1.9±0.3. The adjusted mean difference between treatment groups was 3.3±0.4 (p<0.0001). Secondary endpoints of number of CSBM, number of SBM, and a range of constipation-associated symptoms were all statistically significant in favour of bisacodyl. Quality-of-life (PAC−QOL©) change from baseline for the overall score as well as single scores ‘Worries and concerns', ‘Physical discomfort', ‘Psychosocial discomfort' and ‘Satisfaction' were all significantly improved in favour of the bisacodyl group (for ‘Psychosocial discomfort': p=0.007; for all others p<0.0001). Treatment with bisacodyl was well tolerated. All SAEs (occurring in 2 patients on placebo and 1 patient on bisacodyl) were assessed as non-drug-related. CONCLUSION: Oral bisacodyl is an effective, welltolerated and safe treatment for patients with chronic constipation. It increases bowel frequency, frequency of complete bowel actions, and improves the associated symptoms of constipation and disease-related quality of life.
Cytokine secretion as % change from baseline (mean, +/-SEM) * P ≤ 0.05 significant compared to baseline. S1319 Prokinetic Effects of Lubiprostone on Gastrointestinal Motility in Dogs Jun Song, Jieyun Yin, Hanaa S. Sallam, Ruixing Zhang, Jiande Chen Aims: The study aimed to explore possible prokinetic effects of a chloride channel activator, Lubiprostone on gastrointestinal motility in healthy dogs. Methods: Six healthy female hound dogs were chronically implanted with two cannulas, one at the proximate jejunum and the other at the proximate ascending colon. A number of experiments were performed to access the effects of Lubiprostone (Lub.) on gastric emptying, small intestinal transit and contractions, and colon transit and contractions in these dogs. Gastric emptying of solids was determined by the collection of gastric chyme from the jejunum cannula after ingestion of a can of dog food in three randomized sessions (control and 2 doses of Lub.). Small bowel transit time was studied by observing the time from the injection of phenol red into the jejunum cannula till the first appearance of phenol red from the colon cannula. Colon transit was evaluated by inserting radiopaque markers into the colon from the colon cannula and taking X-ray pictures at 2,4 and 6hrs after the insertion of the markers. Small bowel and colon contractions were measured via a water-perfuse catheter inserted into the small bowel or colon via the corresponding cannula. Each of the experiments was performed in two or three randomized sessions: control, Lub.24μg, or/and Lub.48μg. Lub. was orally administrated 45 minutes before the experiment. Results:1) Lub. significantly accelerated gastric emptying of solids at a dose of 48μg (empertying at 120min: 72.2±7.7% vs. 53.1±5.8% with control, p=0.02 ) but not at 24μg. 2) Lub. significantly reduced small bowel transit time at both 48μg (82.5±31.3 min vs. 137.8±19.3 min, P<0.05) and 24μg (71.0±28.9 min, P<0.05 vs. control). 3) Lub. at 48μg significantly accelerated colonic transit. The geometric center value at 4hrs after the insertion of the markers was 5.1±0.3 with Lub. and 4.3±0.4 in the control session (P=0.047). 4) The manometric studies showed that lub. 48μg significantly increased postprandial small bowel motility index (8.8±0.6 vs.13.2±1.5, P=0.006) and colon motility index (5.8±0.5 vs. 7.3±0.8, P=0.048). Conclusion: Lubiprostone accelerates gastric emptying of solids, small bowel transit and colon transit, and enhances small intestinal contractions and colon contractions in the postprandial states. Theses findings suggest that Lubiprostone may be used to treat patients with gastrointestinal motility disorders. More studies are needed to investigate the mechanisms involved in the prokinetic effects of Lubiprostone.
AGA Abstracts
S1322 Effects of Lubiprostone on Serotonin Release From the Intestinal Mucosa Elice M. Brooks, Jill M. Hoffman, Vanessa W. Hui, Gary M. Mawe Lubiprostone is a selective activator of type-2 voltage-activated chloride channels (ClC-2) located on intestinal epithelial cells, and it alleviates constipation by enhancing intestinal secretion. Lubiprostone is generally well tolerated, but nausea is the most frequently occurring side effect. Serotonin (5-hydroxytryptamine; 5-HT) release from the mucosa of the upper gastrointestinal tract can induce nausea by activating 5-HT receptors on vagal afferent fibers, and this is alleviated by treatment with 5-HT3 receptor antagonists. Serotonin release from enterochromaffin (EC) cells also stimulates secretion and motility via activation of intrinsic neural reflexes. Therefore, this study was designed to test whether EC cells express ClC-2 channels, and if lubiprostone causes release of 5-HT from these cells. Double-label immunohistochemistry for ClC-2 and 5-HT was performed to determine whether ClC-2 channels are located on EC cells, and enzyme immunoassay was used to test whether lubiprostone elicits 5-HT release from the intestinal mucosa. Immunohistochemistry involving the use of two different polyclonal antisera directed against the ClC-2 channel revealed ClC-2 immunoreactivity on EC cells in the mucosa of the human rectum and guinea pig distal colon. In the 5-HT release studies, 5 minute exposure to lubiprostone (1 μM) did not stimulate 5-HT release in human rectal mucosal biopsy specimens or guinea pig duodenal mucosal preparations, but lubiprostone did cause a slight but significant increase in 5-HT release in guinea pig distal colon mucosal samples. The 5-HT release elicited by lubiprostone in the distal colon preparations was less than that detected in positive control experiments involving mechanical stimulation (agitated on a vortex) or syrup of ipecac (1:10 dilution in Krebs solution). In conclusion, these data indicate that EC cells express ClC-2 channels, but activation of these channels by lubiprostone is not a very effective trigger for 5-HT release. This study was supported by Takeda Pharmaceuticals and NIH grant DK62267.
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